COMPARISON OF THE RESPIRABLE FRACTION FROM THREE DIFERENT DPI DEVICES

Transcription

1 COMPARISON OF THE RESPIRABLE FRACTION FROM THREE DIFERENT DPI DEVICES Miriam Sanz Cermeño and Helena Maria Cabral Marques UCTF, Faculdade de Farmácia, Universidade de Lisboa, PORTUGAL 1. Introduction Inhalation is a method of delivery which has been known and used for decades, mainly in respiratory diseases. There are two ways of treating asthma: a) to dilate the bronchi, i.e. to treat an asthma attack as it occurs and the drugs used are bronchodilators such as salbutamol; b) to inhibit bronchoconstriction, by attacking the inflammation with steroidal anti-inflammatories. Dry powder inhalers (DPIs) offer a unique opportunity for the delivery of drugs to the lung as aerosols. These devices combine powder technology with device design in order to disperse dry particles as an aerosol in the patient s inspiratory airflow [1]. The deposition of particles is largely controlled by their impaction on pulmonary surfaces. The larger particles (> 20 µm) impact in the oropharynx; the particle velocity increases as the airways become narrower at deeper levels, and successively smaller particles impact in narrower vessels. Thus the terminal bronchioles are only reached by particles smaller than 2-3 µm. Unfortunately these smallest particles may not impact at these deep levels, since they do not diffuse rapidly enough to encounter an epithelial surface before exhalation removes them from the respiratory tract [2]. To introduce drug particles into the lung they must be < 5 µm in aerodynamic diameter [1]. This is generally achieved by milling the powder prior to formulation. Small particles are notoriously difficult to disperse. The forces governing dispersion are well documented and consist mainly of electrostatic, Van der Waals, and capillary forces [1]. One approach that has been taken to improve the dispersion of dry powders is the inclusion of an excipient, notably lactose. The lactose particles are intended to act as carrier particles for the drug and as such are in a much large size range, µm [1]. The drug particles are dispersed and can traverse the upper respiratory tract while the excipient particles do not pass beyond the mouth piece of the device or the mouth and throat of the patient [1]. In order to study better these excepient / drug interations, as dry powders, three devices were compared these work three devices were compared: the Microhaler, the Rotahaler and the FlowCaps.

2 2. Materials and Methods 2.1. Devices The three devices used are capsule-based inhalers: Microhaler TM - the capsule is pierced manually at both ends, using the pin mechanism existing inside the device. The powder is then released through the capsule holes and inhaled through a screened tube by means of the circulating air which generates a rotating motion in capsule (i.e. spinning of the capsule). Rotahaler TM - the capsule is inserted into the device, wherein, by rotating the device it is opened (or broken) in two halves: the capsule body containing the powder falls into the device, while the capsule cap is retained in the entry port (hole) and the powder is inhaled through a screened tube [3]. The capsule body containing the powder experiences an erratic motion in the air stream, causing dislodge particles to be entrained and inhaled [1]. Flowcaps - is based on a new concept in capsule-based inhalers: the dancing cloud which causes the emission of the powder contents of a motionless capsule [4]. The capsule is cut at both ends by blades. As the admission of air into the capsule is severely restricted through very small cuts, i.e. narrow slits, a low pressure is created in that area of the capsule, causing the powder to rush towards it (against the direction of the airflow), and it gradually becomes entrained towards the mouthpiece [4]. The figures represent the 3 devices used: 1) Microhaler TM 2) Rotahaler 3) FlowCaps 2.2. Deposition of salbutamol sulphate The in vitro deposition of pulmonary aerosol formulation was tested using the Twin-stage liquid impinger (Twin Impinger, Copley, U.K.) [5], a two-stage separation device for assessing the drug delivery from inhalation delivery devices. The discharged aerosol is fractionated by firing through a simulated oropharynx and then through an impinger stage of defined aerodynamic particle size cut-off characteristics [6]. The fine (pulmonary) fraction which penetrates is collected by the lower impinger.

3 This glass impinger, in which the aerosol particles impinge on to the liquid and surfaces due to their inertia in a deflected airstream, has proved valuable for routine quality assessment of aerosols during product development, stability testing and for quality assurance and comparison of commercial products [6]. To enable correct functioning of most powder inhalers, a airflow of 60 L min -1 is recommended [5, 6]. The blend tested, salbutamol sulphate and lactose, batch nº F6-9617, was prepared by using a special mixer. The blend particle size distribution obtained by dry dispersion (Malvern Mastersizer) was as follows: 90 % < µm; 50 % < µm and 10 % < µm. Hard gelatine capsules n.º 4 (for the FlowCaps ) and n.º 3 (for the Microhaler and Rotahaler ) were filled with 22 mg (Balance: Mettler AG 204. Delta Range ) of the mixture (corresponding to 200 µg salbutamol per capsule). These capsules were then placed in the Microhaler, Rotahaler or FlowCaps Dry Powder Inhaler devices and tested using the Twinstage liquid impinger [5]: 7 and 30 ml of Hydrochloric acid 0,1 M were introduced into the upper and lower impingement chambers, respectively. The vacuum pump operated for 5 seconds at 60 L/min [6, 5], air flow rate and the capsule content was discharged by the turbulent air stream. Five capsules were fired in succession for each determination. At the end of this operation, the apparatus was disassembled and the inner surfaces were washed separately with Hydrochloric acid 0,1 M. The amount of active substance collected in each of the stages or portions (capsule + DPI device, throat, upper and lower impingement chambers) was assayed by UV spectrophotometry (UV / VIS Spectrophotometer, Hitachi U 2000) at 276 nm, and the salbutamol was quantified. 3. Results and Discussion Besides the results for the respirable fraction (Lower impingement chamber), results obtained for all other compartments of the Twin Impinger: Throat, Upper impingement chamber and also the remaining dose in the capsule and device with the three different devices are shown in the following table: Microhaler Capsule+device Throat Upper Lower Total Determ. 1 11,4 6,5 77,9 12,0 107,8 Determ. 2 10,2 7,1 73,6 9,5 100,4 Determ. 3 11,4 8,3 79,7 8,3 107,7 Average 11,0 7,3 77,1 9,9 105,3 SD 0,7 0,9 3,1 1,9 4,2 rsd 6,3 12,6 4,1 19,0 4,0

4 Rotahaler Capsule+device Throat Upper Lower Total Determ. 1 28,6 13,2 56,3 7,1 105,2 Determ. 2 29,2 12,0 48,3 7,1 96,6 Determ. 3 25,5 13,8 57,6 7,7 104,6 Average 27,8 13,0 54,1 7,3 102,1 SD 2,0 0,9 5,0 0,3 4,8 rsd 7,2 7,1 9,3 4,8 4,7 FlowCaps Capsule+device Throat Upper Lower Total Determ. 1 8,9 17,5 58,8 15,7 100,9 Determ. 2 9,5 18,8 52,6 14,5 95,4 Determ. 3 9,5 18,8 55,7 14,5 98,5 Average 9,3 18,4 55,7 14,9 98,3 SD 0,3 0,8 3,1 0,7 2,8 rsd 3,7 4,1 5,6 4,7 2,8 These results are expressed as the percentage of drug dose filled into one capsule (200 µg). As the DPI devices combine powder technology with device design, different devices may give different results even with the same formulation and in the same conditions. This is one of the reasons for the observed differences between the three devices tested. All these systems have a mechanism for aerosolising the powder. Reproducible dose metering and dispersion characteristics are affected by particle size, rugosity, shape, moisture content, surface chemical composition and charge [1]. As the powder blend tested was from the same batch for all experiments performed in this work (uniformity of content in 20 samples tested had a rsd of less than 4 %), and consequently those characteristics were the same for all determinations, there were small differences intra-device (relative standard deviations are reasonable for most of the compartments: between 3.7 and 5.6% for the FlowCaps, between for 4.8 and 9.3% for the Rotahaler, and between 4.1 and 19.0% for the Microhaler ). The data show that FlowCaps had the best shot-to-shot reproducibility. The induction of turbulent flow in narrow tubes can be associated with an enhanced deaggregation of the powder agglomerates. For this reason internal geometry of the device is of great importance, for example the dimensions of channels through which the inspired airflow passes and the release mechanism of the powder from the capsule. This may cause the differences between the three devices as the Microhaler delivers the dose through a capsule hole made by a pin, the Rotahaler delivers the dose through the open capsule and the FlowCaps delivers the dose through a cut made by a blade.

5 For a more illustrative information the same results are listed out also as the emitted fine particle fraction in the following tables: Microhaler Cap. & Dev.(µg) Stage I (µg) Stage II (µg) Emitted dose (µg) FPF (% < 6.4 µg) % emitted dose % nominal dose Total recovery % nominal dose Determ. 1 22,8 168,8 24,0 192,8 12,4 12,0 107,8 Determ. 2 20,4 161,4 19,0 180,4 10,5 9,5 100,4 Determ. 3 22,8 176,0 16,6 192,6 8,6 8,3 107,7 Average 22,0 168,7 19,9 188,6 10,5 9,9 105,3 SD 1,4 7,3 3,8 7,1 1,9 1,9 4,2 rsd 6,3 4,3 19,0 3,8 18,2 19,0 4,0 FPF (% < 6.4 µg) Total recovery Rotahaler Cap. & Dev.(µg) Stage I (µg) Stage II (µg) Emitted dose (µg) % emitted dose % nominal dose % nominal dose Determ. 1 57,2 139,0 14,2 153,2 9,3 7,1 105,2 Determ. 2 58,4 120,6 14,2 134,8 10,5 7,1 96,6 Determ. 3 51,0 142,8 15,4 158,2 9,7 7,7 104,6 Average 55,5 134,1 14,6 148,7 9,8 7,3 102,1 SD 4,0 11,9 0,7 12,3 0,6 0,3 4,8 rsd 7,2 8,9 4,7 8,3 6,5 4,7 4,7 FPF (% < 6.4 µg) Total recovery FlowCaps Cap. & Dev.(µg) Stage I (µg) Stage II (µg) Emitted dose (µg) % emitted dose % nominal dose % nominal dose Determ. 1 17,8 152,6 31,4 184,0 17,1 15,7 100,9 Determ. 2 19,0 142,8 29,0 171,8 16,9 14,5 95,4 Determ. 3 19,0 149,0 29,0 178,0 16,3 14,5 98,5 Average 18,6 148,1 29,8 177,9 16,7 14,9 98,3 SD 0,7 5,0 1,4 6,1 0,4 0,7 2,8 rsd 3,7 3,3 4,6 3,4 2,4 4,6 2,8 where: Emitted dose = Stage I + Stage II Fine Particle Fraction (FPF) % emitted = ((Stage II)/(Stage I + Stage II))*100 Fine Particle Fraction (FPF) % nominal = (Stage II/nominal dose)*100 Total Recovery = Capsule and device retention + Stage I + Stage II Nominal dose = capsule content i.e. 200 µg

6 The Rotahaler TM not only has poor emptying performance (showed by the high amount retained in device and capsule), but also a poor aerosolisation efficiency (as a low % FPF was obtained). Both Microhaler TM and FlowCaps have good emptying efficiencies (as showed by the low amount retained) and Flow Caps has the higher % FPF (is it significantly different, p < 0.05). The data seems to support Hovione's claim that by designing a device where the capsule is stationary so all possible energy from patient's inhalation is directed to aerosolising the powder (rather than rotate and/or shake the capsule too), an improved performance can be obtained. It should be noted that the FlowCaps device used in this work (code-named Dolphin) was not yet in the market and at the moment Hovione has evolved the FlowCaps device (code-named Midget) which resulted from an improvement / upgrading of the former device. 4. Conclusions FlowCaps seems to be the best device for the salbutamol sulphate - lactose mixture used, under our working conditions if compared to the Microhaler TM and Rotahaler TM. The results obtained with the devices can be ranked in the following order: FlowCaps > Microhaler TM > Rotahaler TM. 5. References Hickey, A. J., "Inhalation Aerosols: Physical and Biological Basis of Therapy ". Marcel Dekker, New York P: Swarbrick, J., Boylan, J.C., "Encyclopaedia of Pharmaceutical Technology" Vol. 12. P: 160, Swarbrick, J., Boylan, J.C., "Encyclopaedia of Pharmaceutical Technology" Vol. 9. P: and Villax, P., Brito, V., McDerment, I. "A Capsule-based dry powder inhaler". In: FlowCaps Information Pack. DY002-rev. 5. June P:1-4. Eur. Pharm rd edition. P: 144. Hallworth, G.W., Westmoreland, D.G. "The Twin-Impinger: a simple device for assessing the delivery of drugs from metered dose pressurized aerosol inhalers". J. Pharm. Pharmacol. 1987, 39:

7 6. Acknowledgements We gratefully acknowledge Hovione - Produtos Farmacêuticos S.A. for providing the FlowCaps device. This work was partially supported by the SOCRATES / ERASMUS European Programme.